This application is a 371 of PCT/EP99/00994 filed Feb. 16,1999.
The invention relates to orally administrable galenic forms comprising one or more active ingredients which are hydrophilic or ionizable in physiological media in combination with one or more excipients. These galenic forms are preferably solid forms such as tablets or gelatin capsules. The galenic compositions of the invention are particularly advantageous in that they allow improved absorption of active ingredients which are hydrophilic and/or ionizable in physiological media, by the transmembrane or paracellular route, because of their particular excipient composition.
The absorption of orally administered active ingredients essentially takes place by the transmembrane or paracellular route at the level of the mucous membranes of the gastrointestinal tract. In the case of active ingredients which are hydrophilic or ionizable in physiological media, the absorption predominantly takes place by the paracellular route. Because of this, the bioavailability of this type of active ingredient is very low, the kinetics of absorption being very slow. Numerous authors have more precisely studied the kinetics of absorption of active ingredients in the form of calcium salts and have observed that the transport of these substances by the paracellular route is very limited: it appears that the calcium salts have the effect of closing again the channels present between the cells which provide for transport by the paracellular route. Reference may be made, for example, to P. Artursson and C. Magnusson, J. Pharm. Sci., 79, 595, 1990 and S. G. Milton and V. P. Knutson, J. Cell. Physiol., 144, 498, 1990.
The use of various excipient systems comprising liquid or amphiphilic compounds such as semisynthetic glycerides for promoting the absorption of active substances has been abundantly illustrated in the art. In this regard, there may be mentioned the following state of the art documents: WO 93/00891, EP 670 166, WO 95/08 983, WO 94/23 733 and WO 96/21 439. All the prior art formulations are intended, however, to improve the bioavailability of lipophilic active substances. Moreover, the formulations provided in the case of tablets, granules or microgranules do not always allow control of the kinetics of release.
This may result in an intense increase in the plasma concentration, which is quite often followed, in the case of compounds having a short half-life, by a rapid decrease in these levels which reach values below the therapeutic threshold. Multiplication of the number of doses is then necessary in order to maintain a therapeutic effect for the medication.
However, control of the absorption of the active ingredients at the level of the gastrointestinal tract will ensure the efficacy of the therapy used. Furthermore, modulation of the release (while preserving an optimized absorption) makes it possible to ensure better therapeutic cover and to improve tolerance and compliance. Thus, it is possible to reduce the number of doses of the medicament and to thereby ensure compliance with the treatment. This is essential in the case of treatment of long-term, or even chronic, disorders or pathologies.
The galenic forms of the invention allow improvement in the absorption of the active ingredients which are hydrophilic and/or ionizable in physiological media, the control of the kinetics of release and the maintenance of the yield of absorption, this being also in the case of solid pharmaceutical forms such as tablets, gelatin capsules or microgranules.
Although the galenic forms of the invention are particularly appropriate for the administration of active substances which are hydrophilic and/or ionizable in physiological media, they are also suitable for the administration of lipophilic substances.
It may also be noted that the pharmaceutical dosage forms of the invention ensure excellent reproducibility of the results, while allowing increased control of the rate of release during the phase of prolonged release of the active ingredient. By using the pharmaceutical dosage forms of the invention, it becomes possible to optimize the availability of the active ingredients in the body taking into account both the tolerance of the subject to the active ingredient and the pharmacokinetic and metabolic profiles of the active ingredient.
The tablets of the invention are moreover advantageous from the point of view of the formulation of the active ingredients since a judicious choice of the excipients leads to tablets with high concentrations of active ingredients.
The invention provides more precisely orally administrable galenic forms comprising an active ingredient which is hydrophilic and/or ionizable in physiological media, an absorption-promoting agent having an HLB (hydrophilic/lipophilic balance value) greater than 8 and one or more pharmaceutically acceptable excipients.
It should be understood that the galenic forms comprising captopril as active ingredient are excluded from the subject of the invention.
According to the invention, the absorption-promoting agent consists of one or more lipid substances chosen from:
polysorbates; ethers of polyoxyethylene and alkyl; esters of polyoxyethylene and fatty acids; fatty acids; fatty alcohols; bile acids and their salts with pharmaceutically acceptable cations; esters of C1-C6 alkanol with fatty acids; esters of polyol with fatty acids, the said polyol comprising from 2 to 6 hydroxyl functional groups; polyglycolysed glycerides.
These lipid substances are of natural or synthetic origin, or alternatively are obtained by semisynthesis. A good number of them are commercially available or are easily prepared from commercial products.
Although the inventors do not intend to be limited to any mechanism of action, it is thought that by acting on the surface tension of biological fluids, these substances act on membrane contacts at the level of the cells of the gastrointestinal mucous membrane. Whatever the case, it is thought that the absorption-promoting agent creates in situ an environment with modified lipophilicity.
The polysorbates are esters of fatty acids of polyethoxylated sorbitan. Polyethoxylated sorbitan offers polyethoxylated sorbitol and polyethoxylated sorbitol anhydrides. The expression xe2x80x9cpolysorbatexe2x80x9d designates both mono- and polyesters of fatty acids. Preferably, the polysorbates used according to the invention are mono-, di- or triesters of saturated or unsaturated fatty acids, in which the fatty acids are preferably C8-C22, better still C12-C18. There may be mentioned more particularly monolaurate, monopalmitate, mono- and tristearate, monooleate and monoisostearate.
Preferably, the polysorbates used are the product of the esterification of fatty acids with the copolymer of a molecule of sorbitol or of one of its anhydrides and of 3 to 30 molecules of ethylene oxide.
By way of example, the structural formulae of a monoester and of a triester are given below: 
where R is the residue of a fatty acid and x, y, z and w are integers whose sum varies between 3 and 30, preferably between 4 and 20.
Generally, polysorbates will be used whose molecular weight varies between 450 and 2000, better still between 500 and 1900.
Such polysorbates are commercially available, especially under the trade name Tween(copyright).
The ethers of polyoxyethylene and alkyl have the general formula:
CH3(CH2)xc3x97(OCH2CH2)yOH
in which x is an integer between 8 and 22, preferably between 12 and 18, and y is an integer from 10 to 60. Among these compounds, there may be mentioned monocetyl ether of polyethylene glycol, monolauryl ether of polyethylene glycol, monooleyl ether of polyethylene glycol and monostearyl ether of polyethylene glycol. These compounds are commercially available, especially under the trade name Brij(copyright).
The esters of polyoxyethylene and fatty acids are either fatty acid monoesters of the formula:
RCOxe2x80x94(OCH2CH2)nxe2x80x94OH
where R represents the residue of a fatty acid and n the degree of polymerization of the polyethoxylated chain,
or fatty acid diesters of formula:
RCOxe2x80x94(OCH2CH2)nxe2x80x94OCOR
where R and n are as defined above,
or mixtures of these monoesters and of these diesters. These compounds are commonly prepared from the corresponding fatty acids and polyethylene glycols.
The polyethylene glycols used as starting material have variable average molecular masses of between 100 and 7000, preferably between 150 and 6000. The starting fatty acids are saturated or unsaturated and generally have from 8 to 22 carbon atoms, better still from 12 to 18 carbon atoms. The esters of polyoxyethylene and fatty acid are especially marketed by the company AKZO-NOBEL
The fatty alcohols which can be used according to the invention are saturated or unsaturated, and have preferably from 8 to 22 carbon atoms, better still from 12 to 18 carbon atoms.
The fatty acids are saturated or unsaturated, and have preferably from 8 to 22 carbon atoms, or better still from 12 to 18 carbon atoms.
The bile acids are well known to persons skilled in the art. There may be mentioned glycocholic acid and taurodeoxycholic acid as preferred bile acids. Within the framework of the invention, the promoting agent may comprise a bile acid salt obtained by reacting this acid with a pharmaceutically acceptable base. The salts of alkali and alkaline-earth metals are particularly advantageous, such as sodium glycocholate.
The esters of C1-C6 alkanol with fatty acids can also be used as absorption-promoting agent. Preferably, the fatty acids leading to these esters are as defined above.
The polyol esters are obtained by condensation of one or more fatty acids, as defined above, with a polyol comprising 2 to 6 hydroxyl functional groups. Among these esters, those obtained by esterification of glycols, polyglycerols, sorbitol or its anhydrides are particularly preferred. As glycol, propylene glycol may be mentioned.
The esters of sorbitol or of its anhydrides with one or more fatty acids are fatty acid esters of sorbitan, especially marketed under the trade mark Span(copyright).
The polyglycolysed glycerides are mixtures of glycerides of fatty acids and of esters of polyoxy-ethylene with fatty acids. In these mixtures, the fatty acids are saturated or unsaturated C8-C22, for example C8-C12 or C16-C20. The glycerides are mono-, bi- or triglycerides or mixtures thereof in any proportions. Polyglycolysed glycerides are marketed especially by the company Gattefosse under the trade names Labrafil(copyright), Labrasol and Gelucire(copyright).
According to the invention it is essential that the absorption-promoting agent has an HLB greater than 8. Preferably, the HLB is greater than 10; better still it varies between 12 and 16. It should be understood that when the absorption-promoting agent consists of a mixture of several lipid substances, it is the mixture of these substances which should have an HLB greater than 8.
The preferred galenic forms of the invention are those for which the absorption-promoting agent comprises at least one polyglycolised glyceride, especially at least one polyglycolysed glyceride having an HLB of between 12 and 16.
Advantageously, the absorption-promoting agent comprises, in combination with one or more polyglycolysed glycerides, an ester of sorbitan with one or more fatty acids. By way of illustration, the absorption-promoting agent consists of a mixture of one or more polyglycolysed glycerides and a sorbitan ester with a C8-C22 fatty acid, preferably a C16-C20 fatty acid also having an HLB of between 12 and 16. Among the referred sorbitan esters, there may be mentioned sorbitan monolaurate, sorbitan trilaurate, sorbitan monoisostearate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesqui-isostearate, sorbitan sesqui-oleate, sorbitan trioleate and sorbitan tristearate.
Particularly advantageous examples are:
an absorption promoter consisting of Gxc3xa9lucire(copyright) 44/14;
an absorption promoter consisting of a mixture of Gelucire(copyright) 44/14 and Labrasol(copyright);
an absorption promoter consisting of a mixture of Gelucire(copyright) 44/14, Labrasol(copyright) and an ester of sorbitan with a C16-C20 unsaturated fatty acid, such as sorbitan trioleate.
It should be noted that the lipid substances constituting the absorption-promoting agent may also play the role of lubricant, of wetting agent, of thickening agent or of plasticizer.
Thus, glyceryl monostearate and glyceryl palmitostearate have a good lubricating power. Glyceryl monooleate and the fatty acid esters of polyethoxylated sorbitan play the role of wetting agent and the C16-C20 fatty alcohols and fatty acids (stearic acid, cetyl alcohol), glycerol palmitostearate and more generally some fatty acid glycerides among the monoglycerides, diglycerides and triglycerides are also thickeners. In the same manner, the medium- or short-chain triglycerides act as plasticizers.
Finally, the esters of fatty acid and sorbitan (marketed for example under the name Span(copyright)) and the fatty acid esters of polyethoxylated sorbitan (marketed for example under the name Tween(copyright)) can be used as additives which may be incorporated into the semisolid matrix for filling gelatin capsules.
The galenic forms of the invention are more particularly intended to improve the absorption of active ingredients which are hydrophilic and/or ionizable in physiological media corresponding to at least one of the following definitions:
(A) active ingredients comprising at least one and generally two functional groups chosen from carboxylic acid, sulphonic acid, phosphoric acid, phosphonic acid, phosphinic acid and phenol functional groups in free form or ionized form with pharmacologically acceptable cations;
(B) the active ingredients comprising at least one and generally two functional groups chosen from the sulphonic acid, phosphoric acid, phosphonic acid and phosphinic acid functional groups in free form or ionized form with pharmacologically acceptable cations;
(C) the active ingredients in the form of calcium salts;
(D) the active ingredients which have the formula (I) 
xe2x80x83in which
X is chosen from: 
R being a C1-C7 alkyl radical,
R1, R2, R3 are chosen from hydrogen and a C1-C7 alkyl radical,
A represents a group of formula: 
with v and w=0, 1, 2
or a group of formula 
R5, R6 being chosen, independently of each other, from hydrogen, a C1-C7 alkyl radical, an aryl radical having from 6 to 14 carbon atoms and a heteroaryl radical chosen from furyl, thienyl and thiazolyl, it being possible for the aryl and heteroaryl radicals to carry 1 to 3 substituents chosen from a C1-C7 alkyl group, a halogen or a trifluoromethyl group, and t=1-3,
R4 is chosen from hydrogen, a C1-C7 alkyl radical, a CF3 radical, an aryl radical having from 6 to 14 carbon atoms and a heteroaryl radical chosen from furyl, thienyl and thiazolyl, it being possible for the aryl and heteroaryl radicals to carry 1 to 3 substituents chosen from a C1-C7 alkyl group, a halogen or a trifluoromethyl group,
M represents a monovalent metal (Na, K, Li) or a divalent metal (Ca, Mg, Sr, Zn),
m=1 or 2,
p=1-2 and q=1-2, p and q being such that the electrical neutrality of the salt is ensured.
Among these, the following are particularly preferred:
those for which X=
those for which X=
xe2x80x83the following compounds:
calcium 3-acetylamino-1-propanesulphonate (or calcium acamprosate)
calcium 3-(2-(methyl)propanoylamino)propanesulphonate
magnesium 3-(2-(methyl)propanoylamino)propanesulphonate
calcium 3-(butanoylamino)propanesulphonate
magnesium 3-(butanoylamino)propanesulphonate
calcium 3-(acetylamino)pentanesulphonate
calcium 3-(pentanoylamino)propanesulphonate
calcium 3-(benzoylamino)propanesulphonate
magnesium 3-(benzoylamino)propanesulphonate
strontium 3-(acetylamino)propanesulphonate
zinc 3-(2-(methyl)propanoylamino)propanesulphonate
strontium 3-(2-(methyl)propanoylamino)propanesulphonate
calcium 3-(3-(methyl)propanoylamino)propanesulphonate
magnesium 3-(3-(methyl)butanoylamino)propanesulphonate
calcium 3-(2,2-(dimethyl)propanoylamino)propanesulphonate
magnesium 3-(2,2-(dimethyl)propanoylamino)propanesulphonate
calcium 3-(acetylamino)-2-methylpropanesulphonate
calcium 3-(acetylamino)-3-methylpropanesulphonate
magnesium 3-(acetylamino)-3-methylpropanesulphonate
calcium 3-(acetylamino)-1-methylpropanesulphonate
calcium 3-(acetylamino)-2-phenylpropanesulphonate
calcium 2-(2-acetylaminomethyl)phenylmethanesulphonate
calcium N-(methyl-3-(acetylamino)propanesulphonate
calcium (3-(acetylamino)propyl) ethylphosphinate
calcium 3-(acetylamino)-2-dimethylpropanesulphonate
calcium 3-(trifluoromethylcarbonyl)propanesulphonate;
(E) the active ingredients which are guanidines or guanylguanidines such as metformin or any one of its pharmaceutically acceptable salts and especially metformin hydrochloride;
(F) the active ingredients which are pharmaco-logically acceptable salts of primary, secondary and tertiary amines, such as hydrochlorides, hydrobromides, maleates, acetates, succinates, propionates, fumarates and oxalates;
(G) the active ingredients which, in free form or ionized form with the pharmacologically acceptable cations or anions present in the physiological media, have a solubility greater than 100 g, preferably greater than 250 g per litre;
(H) the active ingredients which, in free form or ionized form with the pharmacologically acceptable cations or anions present in the physiological media, have a partition coefficient D (octanol/water) corresponding to the relationship log10D less than 0, preferably log10D less than xe2x88x920.5, or better still log10D less than xe2x88x9220.
The partition coefficient D is determined in a conventional manner using the xe2x80x9cshake flaskxe2x80x9d technique.
A known quantity of product is introduced into a container containing octanol and water in equal parts (100 ml of water; 100 ml of octanol; the quantity of active ingredient being about 10xe2x88x923 M). The mixture is stirred until the product reaches its equilibrium state between the two phases. The phases are then separated. The product may be assayed in both phases by various known methods adapted to the nature of the active ingredient (spectrometry, chromatographic techniques) The partition coefficient D is given by the equation:
Log D=log (Coct/Caq)
where
Coct: concentration of active ingredient in the octanolic phase;
Caq: concentration of active ingredient in the aqueous phase.
As particularly preferred active ingredients, there may be mentioned metformin and acamprosate as well as their pharmacologically acceptable salts.
The pharmacologically acceptable salts are those commonly used in the art. The alkali and alkaline-earth metal salts are examples.
The quantity of active ingredient present in the galenic forms of the invention varies between 0.001 and 95% by weight, preferably between 0.01 and 90%, or better still between 0.1 and 90%.
Depending on the desired effect, persons skilled in the art will incorporate into the galenic compositions of the invention a larger or smaller quantity of absorption-promoting agent. In the general case, the ratio of the active ingredient(s) to the absorption-promoting agent is between 0.001 and 10, for example between 0.01 and 10.
The galenic forms of the invention may be provided in a solid form of the tablet or gelatin capsule type. When the galenic form is a tablet, the ratio of the active ingredient(s) to the absorption-promoting agent is between 1 and 10.
When the galenic form is a gelatin capsule, the ratio of the active ingredient(s) to the absorption-promoting agent is between 0.1 and 2.
The tablets according to the invention may comprise, in combination with the absorption-promoting agent, one or more additional excipients so as to obtain mono- or polyphase tablets. Persons skilled in the art will choose these excipients according to the desired final properties, the application envisaged or so as to overcome a disadvantage linked to the method of manufacturing the tablets.
These excipients exist especially among the following categories: diluents, binders, lubricants, antioxidants, colorants, sweeteners, flavourings and acidulants, wetting agents, hydrophilizing agents such as sorbitol and cyclodextrins, osmotic agents such as mannitol, pH regulators, stabilizing agents such as trehalose and mannitol, adsorbants, chelating and sequestering agents and gastro-resistant film-coating excipients of the type including cellulose acetyl phthalate and polymethacrylates.
By way of example, any one of the following diluents or a combination thereof may be chosen: calcium carbonate, calcium sulphate, sucrose, dextrates, dextrin, dextrose, dicalcium phosphate dihydrate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, cellulose, microcrystalline cellulose, sorbitol, starches, pregelatinized starch, talc, tricalcium phosphate and lactose.
Among the binders, there may be mentioned: gum arabic, gum tragacanth, guar gum, alginic acid, sodium alginate, sodium carboxymethylcellulose, dextrin, gelatin, hydroxyethylcellulose, hydroxypropylcellulose, liquid glucose, magnesium and aluminium silicate, maltodextrin, povidone, pregelatinized starch, starch and zein.
The lubricants are glidants (such as anhydrous silicate, magnesium trisilicate, magnesium silicate, cellulose, starch, talc or tricalcium phosphate) or alternatively antifriction agents (such as calcium stearate, hydrogenated vegetable oils, paraffin, magnesium stearate, polyethylene glycol, sodium benzoate, sodium lauryl sulphate, fumaric acid, stearic acid or zinc stearate and talc).
As examples of antioxidants, persons skilled in the art can select any of the following compounds: ascorbic acid, ascorbyl palmitate, fumaric acid, propyl gallate, sodium ascorbate and sodium metabisulphite, alpha-tocopherol, malic acid, butylated hydroxytoluene (BHT) and butylated hydroxyanisol (BHA).
Preferred wetting agents are:
sodium docusate and sodium lauryl sulphate which are anionic surfactants;
benzalkonium chloride, benzethonium chloride and cetrimide, which are cationic surfactants;
polyvinyl alcohol and sorbitans, which are non-ionic surfactants.
Among the pH regulators, there may be mentioned acidifiers of the type including citric acid, hydrochloric acid, lactic acid, tartaric acid, as well as alcalinizing agents of the type including monoethanolamine, diethanolamine and triethanolamine, potassium citrate, sodium bicarbonate, sodium citrate dihydrate.
Examples of adsorbants are bentonite, anhydrous colloidal silica, kaolin, magnesium and aluminium silicate, microcrystalline cellulose and cellulose.
As chelating and sequestering agents, there may be used citric acid monohydrate, edetic acid, disodium phosphate, monosodium phosphate, potassium citrate, tartaric acid and sodium citrate dihydrate.
The quantities of these additives are those usually used in the art. In general, the binder may represent from 0.5 to 25% by weight, or better still from 2 to 5% by weight of the tablet.
The lubricants are preferably incorporated into this tablet in an amount of 0.01 to 10% by weight.
As a guide, the quantity of gastro-resistant film-coating excipients varies between 0.5 and 9% by weight of the tablet.
These tablets may be bare, but are preferably film-coated. The film-coating envisaged will make it possible to avoid an unpleasant taste by bringing about masking of the taste. It may participate in modifying the release of the active ingredient and/or of the promoting agent. A gastro-resistant film-coating will make it possible to avoid any release in the stomach; a film-coating which is more hydrophobic and insensitive to pH variations will contribute more towards extending the kinetics of dissolution. Depending on the role attributed to the film-coating, persons skilled in the art will be able to choose the film-forming agent from among the following categories: cellulose derivatives such as hydroxypropylmethylcellulose (HPMC), ethyl cellulose, cellulose acetophthalate, cellulose acetopropionate, cellulose trimelliate, the polymers and copolymers of methacrylic acid and its derivatives. The film-forming agent may be supplemented with:
plasticizers (such as polyoxyethylene glycols of high molecular weight, esters of polyacids such as citric acid or phthalic acid)
fillers (such as talc, metal oxides such as titanium oxide)
colorants chosen from those usable and approved by the pharmaceutical and food industries.
The tablets of the invention are conventionally prepared by a method including the steps of granulation followed by compression. More precisely, the method of manufacture which is the subject of the invention comprises the steps consisting in:
a) preparing a granule of an active substance from a pulverulent mixture of the active substance, to which there would have been added the absorption-promoting agent, preferably in liquid form, agents modifying the kinetics of dissolution, a binding agent and any other excipient which persons skilled in the art will judge to be necessary. The granule formed is called the inner phase.
b) preparing, where appropriate, a pulverulent mixture, termed outer phase, comprising for example cohesion agents, glidants, lubricants.
c) combining, by mixing, the inner and outer phases. It should be noted that all of the constituents of the outer phase may be added and mixed with the excipients of the inner phase during the preparation of the granule ready to be compressed.
d) forming the tablet by compressing the mixture.
Step (a) involves the granulation of powders of amorphous or crystallized particles. This granulation is carried out in a manner known per se and, for example, by a wet granulation method.
The granulation method comprises five essential steps: (i) dry mixing of the various constituents, (ii) wetting, (iii) actual granulation, (iv) drying, and then (v) sizing.
The dry mixing consists of mixing the pulverulent excipients entering into the composition of the granules.
The wetting consists of adding to the pulverulent mixture the various constituents, a wetting liquid which may be water, or an aqueous or organic solution of binder or an alcohol. This is carried out in a mixer-kneader of the planetary, roller, projection or whirling type or a mixer-granulator of the rapid type.
In step (a), the appropriate wetting liquid is water or an alcohol or an aqueous or organic solution of binder, as generally recommended in the art.
According to a particularly preferred embodiment, the absorption-promoting agent is used as wetting liquid for the granulation.
The drying may be carried out in an oven, or in a fluidized air bed dryer, or by microwave.
According to a preferred embodiment of the invention, the sizing is carried out by passing over a screen with a mesh opening of between 0.5 and 1.5 mm, preferably between 0.8 and 1.5 mm.
A preferred mesh opening value is 1.25 mm.
However, the invention does not intend to be limited to the use of a wet granulation method. Thus, persons skilled in the art will also be able to use other existing granulation methods, such as the dry granulation method.
The last step of compression (step d) on an alternating or rotary machine leads to the formation of the tablet.
The galenic forms of the invention may be provided in the form of gelatin capsules or any other substitute material, which may be monolithic, mono- or polyphasic. The content of the gelatin capsule is a matrix of the semisolid type. In this matrix, the active ingredient may be present in dissolved form or alternatively in suspension. The said matrix comprises the absorption-promoting agent described above, the active ingredient and optionally one or more additional excipients chosen from those described below so as to give the preparation the desired properties or so as to overcome the disadvantages linked to the process of preparing the gelatin capsules.
The additional excipients which may be incorporated into the semisolid matrix in combination with the mixture of absorption-promoting agents are of the following categories.
Wetting agents among which are phospholipids such as the derivatives of phosphatidylcholine or phosphatidylethanolamine better known by the name of natural or purified lecithins.
Anionic surfactants, such as sodium alkylsulphonates (such as sodium lauryl sulphate or sodium docusate), cationic surfactants such as quaternary ammoniums (such as benzalkonium chloride or benzethonium chloride or cetrimide).
Thickening agents of the lipid type, among which are vegetable oils (cotton seed, sesame and groundnut oils) and derivatives of these oils (hydrogenated oils such as hydrogenated castor oil, glycerol behenate).
Thickening agents of the waxy type such as natural carnauba wax or natural beeswax, synthetic waxes such as cetyl ester waxes.
Thickening agents of the amphiphilic type such as polymers of ethylene oxide (polyoxyethylene glycol of high molecular weight between 4000 and 100000) or propylene and ethylene oxide copolymers (poloxamers).
Thickeners of the cellulosic type (semisynthetic derivatives of cellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, of high molecular weight and high viscosity, gum) or any other polysaccharide such as alginic acid.
Thickening agents of the polymeric type such as acrylic acid polymers (such as carbomers).
Thickening agents of the mineral type such as colloidal silica, bentonite.
Antioxidants such as ascorbic acid, ascorbyl palmitate, fumaric acid, sodium ascorbate, sodium metabisulphite.
It will be noted that the thickening agents may be added to the mixture of promoting agents in an amount of 0.1 per 1 to 10 per 1. The ratio which exists between the mixture of promoting agents and the mixture of thickening agents determines directly, for the same active ingredient, the kinetics of dissolution of the latter.
The monolithic gelatin capsules of the invention are conventionally prepared by a method including a phase of preparing a semisolid matrix followed by casting into a gelatin capsule.
More precisely, the semisolid matrix is prepared by dispersing, with stirring, the active ingredient in the mixture of the various excipients. The use of subsidiary heating of the container of mixture may be necessary in order to maintain this mixture of excipients in a liquid or semi-pasty state until the phase of casting into a gelatin capsule.
Furthermore, it may be envisaged to cast successively in the same gelatin capsule several semisolid matrices, differing from each other by their active ingredient and/or excipient compositions, thus making possible immediate- and prolonged-type releases which can be adjusted according to pharmacokinetic criteria.
Finally, the method of manufacture may be completed, where appropriate, by sealing the gelatin capsule by bandrolling or any other equivalent system.
It should also be noted that the gelatin capsule form may be replaced by a soft gelatin capsule form or any other substitute material. All the information cited above for the gelatin capsule, both in terms of composition and preparation of the semisolid matrix, remain applicable in this case.
The galenic forms of the invention may be provided in the form of microgranules which may be packaged in a unit dose such as a gelatin capsule, a cachet or a sachet, or even a vial. In this case, the microgranules are obtained by combining the active ingredient and the absorption-promoting agent with one or more excipients chosen from the following categories:
Diluents such as calcium carbonate, calcium sulphate dihydrate, sucrose, lactose, dextrates, dextrin, dextrose, dicalcium phosphate dihydrate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, microcrystalline cellulose, sorbitol, mannitol, starches, talc, tricalcium phosphate.
Thickening agents of the lipid type, among which are vegetable oils (cotton seed, sesame and groundnut oils) and derivatives of these oils (hydrogenated oils such as hydrogenated castor oil, glycerol behenate).
Thickening agents of the waxy type such as natural carnauba wax or natural beeswax, synthetic waxes such as cetyl ester waxes.
Thickening agents of the amphiphilic type such as polymers of ethylene oxide (polyoxyethylene glycol of high molecular weight between 4000 and 100000) or propylene and ethylene oxide copolymers (poloxamers).
Thickeners of the cellulosic type (semisynthetic derivatives of cellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, of high molecular weight and high viscosity, gum) or any other polysaccharide such as alginic acid.
Thickening agents of the polymeric type such as acrylic acid polymers (such as carbomers).
Thickening agents of the mineral type such as colloidal silica, bentonite.
Antioxidants such as ascorbic acid, ascorbyl palmitate, fumaric acid, sodium ascorbate, sodium metabisulphite.
Effervescent mixtures are some of the agents capable of being incorporated into the microgranules. These mixtures are composed, on the one hand, of alkali or alkaline-earth metal carbonates or sodium glycin carbonate, and, on the other hand, of organic acids such as citric acid or tartaric acid. Polymers of the cellulosic type (hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, of high molecular weight and high viscosity) or any other polysaccharide such as alginic acid or of polyacrylic type (carbomers) may also be used in combination. This combination makes it possible to obtain microgranules having good floatability in biological media.
These microgranules may be bare, but are preferably film-coated. The film-coating envisaged will make it possible to avoid an unpleasant taste by bringing about masking of the taste. It may participate in modifying the release of the active ingredient and/or of the promoting agent. A gastro-resistant film-coating will make it possible to avoid any release in the stomach; a film-coating which is more hydrophobic and insensitive to pH variations will contribute more towards extending the kinetics of dissolution. Depending on the role attributed to the film-coating, persons skilled in the art will be able to choose the film-forming agent from among the following categories: cellulose derivatives such as hydroxypropylmethylcellulose, ethyl cellulose, cellulose acetophthalate, cellulose acetopropionate, cellulose trimelliate, the polymers and copolymers of methacrylic acid and its derivatives. The film-forming agent will be supplemented with:
plasticizers (such as polyoxyethylene glycols of high molecular weight, esters of polyacids such as citric acid or phthalic acid)
fillers (such as talc, metal oxides such as titanium oxide).
colorants chosen from those usable and approved by the pharmaceutical and food industries.
The rate of film-coating may vary from 2 to 25% of the weight of the bare microgranules, preferably from 4 to 20% and more preferably from 5 to 20%.
Furthermore, it may be envisaged to fill the same gelatin capsule with different types of microgranules, differing from each other by their active ingredient and/or absorption-promoting agent and/or excipient compositions, or to even combine bare and film-coated microgranules, making it possible to adjust the kinetics of release of the active ingredient.
The microgranules are conventionally prepared by a method including incorporation of the mixture of absorption-promoting agents with the pulverulent mixture of the other excipients and of the active ingredient(s) into a high-speed mixer, followed by nucleation, swelling and spheronization.
As regards the film-coating phase, it is conventionally carried out by spraying a suspension of film-forming agent and additives over a mass of moving microgranules in a turbine or more advantageously in a fluidized air bed apparatus.
The microgranules or a mixture thereof are placed in gelatin capsules in conventional manner using a filling device. For the latter operation, the incorporation of additives such as glidants, lubricants or even diluents may prove necessary. Persons skilled in the art will be able to choose either of these compounds from among the excipients cited in the corresponding paragraphs above.
It should be noted that the microgranules may have a size of between 0.1 and 3 mm, preferably between 0.2 and 2 mm and more preferably between 0.3 and 1.5 mm.
Furthermore, it is possible to envisage the production of tablets from the preceding microgranules. In this case, the cohesion of the tablets can be ensured by virtue of the addition of other microgranules or of a granule prepared in a conventional manner with the excipients conventionally used for this purpose.
In order to easily control the kinetics of release of the active ingredient, it is desirable to incorporate one or more of the following constituents into the galenic forms of the invention:
glycerol palmitostearate;
a hydrogenated castor oil;
glycerol behenate; or
stearic acid.
The addition of polymeric derivatives may also be envisaged for this purpose.
As appropriate polymeric substance, there may be mentioned semisynthetic celluloses of high molecular weight, carbomers such as polyacrylic acids, polymers and copolymers of methacrylic acid and its derivatives.
The examples provided in the remainder of this text illustrate the invention in greater detail. This will be done with reference to FIGS. 1 to 9.
For the sake of simplicity, all the formulations described below have 500-mg doses of active ingredient.